Cardiovascular outcomes between dapagliflozin versus empagliflozin in patients with diabetes mellitus

Abstract Background Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have been demonstrated to decrease cardiovascular adverse events. However, there is little real‐world clinical evidence regarding a direct comparison between dapagliflozin and empagliflozin in patients with diabetes mellitus (DM). Hypothesis A difference in the cardiovascular efficancy of dapagliflozin versus empagliflozin in DM patients was anticipated, aiming to guide the optimal choice of SGLT2 inhibitors based on cardiovascular outcomes. Methods From 2014 to 2020, a total of 1549 patients with DM who were prescribed SGLT2 inhibitors such as dapagliflozin or empagliflozin were retrospectively enrolled. We categorized the study population into two groups: dapagliflozin (n = 981) and empagliflozin group (n = 568). The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of all‐cause death, myocardial infarction (MI), stroke, or hospitalization for heart failure (HF) over a 3‐year period. Results Propensity‐score matching was performed (537 patients in each group). The mean age and hemoglobin A1c were 58.2 ± 13.0 years and 8.4 ± 1.7%, respectively. There was no significant difference between the dapagliflozin and empagliflozin groups in the risk of MACE (3.7% vs. 4.8%, hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.73–2.35; p = 0.349). Furthermore, there were no differences between the two groups in secondary endpoints including all‐cause death, MI, stroke, and hospitalization for HF. Prior MI and history of HF were independent predictors of MACE. Conclusions Dapagliflozin and empagliflozin showed no significant difference of real‐world clinical cardiovascular outcomes in patients with DM over a 3‐year period. Further large randomized clinical trials will be warranted for better evaluation.

period.Further large randomized clinical trials will be warranted for better evaluation.

K E Y W O R D S
dapagliflozin, diabetes mellitus, empagliflozin, major adverse cardiovascular events

| INTRODUCTION
Diabetes mellitus (DM) is a major public health concern globally, known for its association with a spectrum of complications, including atherosclerotic cardiovascular disease and heart failure. 1,2Effective management of blood glucose levels is pivotal in mitigating these risks.Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as dapagliflozin and empagliflozin, have emerged as prominent agents in this context.These inhibitors offer several advantages over traditional glucose-lowering agents, including weight loss and blood pressure reduction without the risk of hypoglycemia. 3,4Crucially, SGLT2 inhibitors achieve glycemic control independently of insulin action, functioning by inhibiting glucose reabsorption in the kidneys and promoting urinary glucose excretion. 5What sets dapagliflozin and empagliflozin apart in the realm of DM management is their documented cardiovascular benefits.7][8][9] Their benefits extend even to patients with heart failure with preserved ejection fraction, as recent studies have shown. 10,11In light of these findings, current guidelines now recommend to use of SGLT2 inhibitors for heart failure patients, irrespective of their ejection fraction status. 12Despite these advances, there exists a notable gap in real-world data, particularly concerning direct comparison between dapagliflozin and empagliflozin in patients with DM.This is especially true in global contexts where these medications are widely prescribed.Addressing this gap is essential for informed clinical decision-making and optimizing patient outcomes.Therefore, our study aimed to fill this void by providing a direct, real-world comparison of the cardiovascular protective effects of dapagliflozin and empagliflozin in patients with DM.Through this research, we seek to contribute valuable insights to the existing literature and aid clinicians in making more informed treatment choices for their patients with DM.

| Study population and data collection
This study was a retrospective observational study that enrolled 2212 diabetic patients prescribed dapagliflozin or empagliflozin from November 2014 to September 2020 at Yeungnam University Medical Center.For this study, 663 patients without follow-up data were excluded.A total of 1549 patients were included in the final analysis.
(Supporting Information S3: Figure 1).The study population was stratified into two groups with respect to prescribed SGLT2 inhibitor: dapagliflozin (n = 981) and empagliflozin (n = 568).Data on baseline medial history, medications, procedural records, and 3-year clinical outcomes were collected from the patients' electronic medical records or direct telephone contact.

| Study endpoints and definitions
The primary endpoint of this study was 3-year major adverse cardiovascular events (MACE).MACE was defined as a composite of all-cause death, myocardial infarction, stroke, or hospitalization for heart failure.The secondary endpoints included individual components of the primary endpoint and hospitalization for ischemic heart disease.Myocardial infarction (MI) was defined as cardiac biomarker elevation with at least one value above the 99th percentile of the upper reference limit, with accompanying ischemic symptoms or electrocardiographic findings indicative of ischemia unrelated to an intervention procedure. 13Stroke was defined as an acute cerebrovascular event resulting in a neurologic deficit >24 h or the presence of acute infarction demonstrated by imaging studies. 14Hospitalization for heart failure was defined as hospitalization requiring at least an overnight stay due to substantial worsening of heart failure symptoms and/or signs, necessitating he augmentation of oral medications or new administration of intravenous heart failure therapy, including diuretics, inotropes, or vasodilators. 15Hospitalization for ischemic heart disease was defined as hospitalization due to the need for coronary revascularization for typical symptoms and signs of electrocardiographic changes, exercise, or pharmacological stress, study evidence for inducible myocardial ischemia, angiographic evidence for new or worsening coronary artery disease and/or intracoronary thrombus, or a hospitalization requiring at least an overnight stay due to substantial worsening of ischemic symptoms and signs (electrocardiographic, echocardiographic, or biomarker changes). 16Chronic kidney disease was defined as an eGFR <60 mL/min/1.73m 2 , including end-stage renal disease with renal replacement therapy.

| Statistical analysis
Baseline patient characteristics were tested using Student's t test for continuous variables and χ 2 statistics for categorical variables.
To minimize the impact of differences in baseline characteristics between two patient groups, the propensity score (PS) matching method was conducted.PS were obtained from logistic regression, including variables that exhibited a significant difference between the two groups (sex, prior MI, prior stroke, hypertension, dyslipidemia, history of heart failure, beta-blocker, ARB/ACE inhibitor, and aspirin use).The Cox proportional hazards regression model was used to calculate the hazard ratio for the primary endpoint and secondary endpoints.In univariate analysis, a Cox proportional-hazards regression model was conducted for several clinical variables, and the variables achieving p < 0.05 in the univariate analysis were entered into the multivariate analysis model to determine independent predictors of MACE.Event-free survival was analyzed using Kaplan-Meier survival curves, and differences between event-free survival curves were compared using the log-rank test.All hazard ratios were calculated with a 95% CI and p < 0.05 was considered statistically significant.The collected data were stored in Excel spreadsheets and statistical analyses were performed using SPSS version 27.0.0(IBM).

| Baseline characteristics
The mean age of the patients was 58.2 ± 13.0 years, and the average hemoglobin A1c level was 8.4 ± 1.7%.The mean follow-up duration was 1227.4 ± 603.4 days.While the mean age was comparable between the two groups (58.3 ± 13.4 vs. 58.0± 12.3 years, p = 0.697), significant differences were noted in sex distribution and medical histories (Table 1).The empagliflozin group had a higher proportion  2, Table 2).A1c level (<9 and ≥9%), hypertension, chronic kidney disease, history of heart failure, and prior MI.No significant differences were observed in the subgroup analysis of the primary endpoint between dapagliflozin and empagliflozin.

| Independent predictors of the primary endpoint
In the total study population, several clinical variables were significantly associated with the prevalence of MACE (

| DISCUSSION
In this study, we demonstrated the favorable 3-year cardiovascular outcome of SGLT2 inhibitors, with a 4.6% occurrence according to the primary endpoint in patients with DM.Additionally, there was no significant difference in the occurrence of MACE between dapagliflozin and empagliflozin.Furthermore, we found that there were no significant differences in all-cause death, cardiovascular death, MI, hospitalization for heart failure, or stroke between the two groups.
Additionally, in diabetic patients prescribed SGLT2 inhibitors, important predictors for cardiovascular outcomes were prior MI and a history of heart failure.
F I G U R E 1 Time-to-event curves of the primary endpoint according to the types of SGLT2 inhibitor (A) in the total population, (B) in the propensity score-matched population.Time-to-event curves were plotted using Kaplan-Meier survival analysis.CI, confidence interval; HR, hazard ratio; MACE, patient oriented composite endpoint; PS, propensity score.
T A B L E 2 Three-year clinical efficacy endpoint according to SGLT2 inhibitors before or after propensity score matching.there was a notable 38% reduction in cardiovascular mortality and a significant 35% decrease in hospitalization for heart failure associated with cardiovascular events. 78][19][20] These findings suggested a class of SGLT2 inhibitors in managing cardiovascular risks in DM patients, irrespective of the specific SGLT2 inhibitors used.However, contrasting outcomes have been observed in some studies.Previous meta-analysis study revealed that empagliflozin might have a more favorable impact on mortality compared to dapagliflozin. 21Additionally, another meta-analysis study also indicated that empagliflozin was more beneficial in reducing mortality and cardiovascular events. 22In contrast, some cohort studies showed no significant difference in overall MACE between the dapagliflozin and empagliflozin, but observed that dapagliflozin might be associated with lower risks hospitalization for heart failure. 23,24The differences in outcomes across various studies might be attributed to differences in baseline comorbidities among the patients enrolled in these studies.As highlighted in previous meta-analysis study, the presence of specific comorbidities in patients might influence the differential efficacy of these SGLT2 inhibitors. 25This suggested that patient-specific factors, including baseline health conditions, could play a crucial role in determining the effectiveness of dapagliflozin and empagliflozin.
In a nationwide cohort study in Korea, it was shown that dapagliflozin might be more favorable in hospitalization for heart failure. 23Although this study enrolled a large number of patients, the proportion of the study population with MI was 2.7%, and history of heart failure was 5.0%, which is lower compared to the landmark studies like EMPA-REG OUTCOME trial and DAPA TIMI 58 trial. 6,7,23pagliflozin group in DAPA TIMI 58 study showed that the rate of comorbidities of heart failure and coronary artery disease was 9.9% and 32.9%, respectively. 6The difference in the presence of comorbidities like MI and history of heart failure was crucial.This presented study demonstrated that independent predictors for MACE were prior MI and history of heart failure.The rate of prior MI and history of heart failure were 13.5% and 15.3% in this presented study.Our study showed that, even in data with more comorbidities such as MI and heart failure, there was no significant difference in cardiovascular outcomes over a 3-year period between dapagliflozin and empagliflozin.
There were several limitations in this study.First, the study was a retrospective observational study based on single-center data, which potentially subjected the findings to selection bias.PS matching was performed to mitigate known confounders and balance baseline characteristics.However, this method primarily addressed observable factors and may not have fully accounted for unmeasured variables that could have influenced clinical outcomes, leading to possible residual confounding.Second, the relatively small sample size of the study could have limited the statistical power and the number of events captured.This limitation was particularly significant in the context of rare outcomes, where larger sample sizes are typically T A B L E 3 Independent predictors of primary endpoint in total population.

Figure 2
Figure 2 presents a forest plot illustrating the comparison of the primary endpoint between dapagliflozin and empagliflozin across various subgroups, including age (<75 and ≥75 years), sex, hemoglobin